Arthritis of primary biliary cirrhosis.

We describe the clinical and roentgenographic findings in the hands of 13 patients with primary biliary cirrhosis. A nondeforming, generally asymptomatic erosive arthritis was present in 12 of 13 patients. The erosions were asymmetrically distributed and mainly involved the distal small joints of the hands. Seven patients had osteopenia due to hepatic osteodystrophy. Intraosseous lytic defects were present in three patients, chondrocalcinosis in two patients, and hypertrophic osteoarthropathy in one patient. We discuss the importance of the clinical and roentgenographic features of the arthritis of primary biliary cirrhosis.     

Treatment of primary biliary cirrhosis.

Although primary biliary cirrhosis (PBC) is generally a progressive disease, the rate of progression varies greatly from one patient to another. The terminal phase is characterized by hyperbilirubinaemia (>100 micromol/l), a major decrease in the number of intrahepatic bile ducts, and extensive fibrosis or cirrhosis. It is now well established that orthotopic liver transplantation is the treatment of choice for patients entering the terminal phase of the disease.A variety of therapeutic agents have been proposed for treatment of patients with PBC. However, most have been found ineffective or too toxic to be widely used. In contrast, there is accumulating evidence from large therapeutic trials that long-term administration of ursodeoxycholic acid (UDCA) is safe and prolongs survival free of liver transplantation. Treatment with UDCA slows the histological progression and delays the onset of cirrhosis.In patients who have a sub-optimal response to UDCA therapy alone, the combination of colchicine or methotrexate with UDCA has minimal or no additional benefit, whereas that with corticosteroids is more promising but not yet demonstrated.Among causes of non-response to UDCA therapy, the most common is the PBC-autoimmune hepatitis overlap syndrome. The benefit from the combination of corticosteroids and UDCA in this setting is obvious.Further studies are needed to define the patients who are most likely to respond to UDCA therapy and to assess the benefit of combined medical treatments.     

Autoimmunity and primary biliary cirrhosis.

The history of primary biliary cirrhosis (PBC) began in 1851, with autoimmunity introduced in 1958 and expanded from the 1960s on. In PBC, autoantibodies are present to mitochondria-located antigens (AMA) and to nuclear-located antigens (ANA). The AMA react with E2 subunits of three members of the 2-oxoacid dehydrogenase complex family, but most frequently with pyruvate dehydrogenase complex (PDC); the inner lipoyl domain of PDC-E2 contains a major B- and T-cell epitope. The ANA react with three nuclear components, centromeric proteins, nuclear dot proteins and nuclear pore complex. Autoimmune diseases including PBC reflect a failure in mechanisms of self-tolerance which is developed in central lymphoid tissues in embryonic life by deletion of self-reactive lymphocytes, and maintained in peripheral tissues in post-natal life by regulatory processes. Primary biliary cirrhosis has not yet been identified with failure in any one particular tolerance mechanism. Genetic influences are revealed by familial occurrences and by associations with HLA alleles, and environmental influences by epidemiological data. A lead to pathogenesis is the accumulation uniquely in PBC of PDC-E2-like material at the plasma membrance of biliary epithelial cells (BECs). Although the origin of this accumulation of PDC-E2 at the surface of BECs is uncertain, it provides a credible 'tissue-specific' target for an autoimmune attack by T and B lymphocytes at the site of the actual pathology.     

Update on primary biliary cirrhosis.

The diagnosis of primary biliary cirrhosis (PBC) is most often made in the asymptomatic phase, sometimes before the development of abnormal liver biochemistry. The antimitochondrial antibody remains the predominant hallmark, although not all patients test positive, even when the most sensitive techniques are used. The etiology of PBC remains elusive; studies suggest that the interlobular bile duct destruction is immune based, and associated autoimmune diseases are common. There are no surrogate markers that predict outcome in asymptomatic patients, whose chance of survival is less than that of age- and sex-matched populations but much better than the median survival of eight years in patients with symptomatic PBC. Symptoms common in this disease are fatigue, pruritus and xanthelasma, as well as complications of portal hypertension and osteoporosis. Treatment includes symptomatic and preventive measures, as well as specific therapeutic measures. Immunosuppressive therapy has yielded disappointing results in the long term management of PBC, and the only therapy shown to improve survival is the hydrophobic dihydroxy bile acid ursodeoxycholic acid. Treatment at a dose of 13 to 15 mg/kg/day is optimal, given in separate doses or as a single dose at least 4 h from giving the oral anion exchange resin cholestyramine, which may be used to control pruritus. However, liver transplantation remains the only cure for this disease, and the best postoperative survival is seen in patients whose serum bilirubin does not exceed 180 micromol/L at the time of liver transplantation. Recurrence takes place but is rarely symptomatic and does not deter from the benefits of transplantation.     

Bacteriuria and primary biliary cirrhosis.

Significant bacteriuria was found in 19% of 87 women with primary biliary cirrhosis, whereas in 89 women with other types of chronic liver disease bacteriuria was present in only 7%. In 74 women with rheumatoid arthritis 8% were bacteriuric. Midstream urine specimens obtained from 144 consecutive women with primary biliary cirrhosis attending hospital over a two year period showed that 50 (35%) developed bacteriuria during 12 months of follow up. Bacteriuria was unrelated to age, raised serum bilirubin, drug therapy or urinary pH but was more common in patients with late stage (fibrotic) disease as judged by histological criteria. Fifty seven per cent of bacteriuric primary biliary cirrhosis patients suffered more than one urinary infection. Fifty nine per cent of the 156 bacteriuric episodes were asymptomatic. The types of organism isolated, the antibiotic sensitivity patterns and cure rate were similar to those reported in bacteriuric women without other underlying disease. The reinfection rate (34%), however, was double that reported for bacteriuric episodes in 'problem' women with recurrent bacteriuria, indicating a special susceptibility to urinary infection. The most common isolates were E coli (70%), which did not show abnormal adhesiveness to uroepithelial or buccal cells of normal women, or to those of primary biliary cirrhosis patients. Patients with primary biliary cirrhosis have not been reported to be more susceptible to infection in general. Bacteriuria, however, was common throughout all clinical stages of primary biliary cirrhosis. Thus there may be a unique association between bacteriuria and primary biliary cirrhosis.     

Immunopathology of primary biliary cirrhosis.

A major advance in the study of primary biliary cirrhosis was identification of the major B-cell auto-antigen as the mitochondrial enzyme pyruvate dehydrogenase dihydrolipoamide acetyltransferase (PDC-E2). Subsequent studies revealed that PDC-E2 also contained epitopes recognized by patients' T cells. Furthermore, aberrant expression of MHC class II, intercellular adhesion molecules, lymphocyte co-stimulatory molecules and B-cell epitopes of PDC-E2 was observed on patients' biliary epithelium, supporting the concept that biliary epithelial cells are the target of a focused autoimmune reaction. Changes in distribution of auto-antigen on biliary epithelium and the presence of auto-antibody in patient's serum have both been shown to occur very early in the natural history of primary biliary cirrhosis, suggesting an intimate role for these molecules in immunopathogenetic mechanisms.     

Recurrent primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis after transplantation

Viral hepatitis and malignancy frequently recur after transplantation, but recurrence of primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and autoimmune hepatitis is controversial. Differences in study design, number of patients, immunosuppressive treatment, length of follow-up, and criteria for recurrence account for discrepant results. Most patients with suspected recurrent disease are asymptomatic after transplantation. In patients transplanted for PBC, antimitochondrial antibodies frequently persist and do not correlate with disease recurrence; liver biopsy remains the gold standard for diagnosis. Exclusion of other disorders that can mimic PBC is paramount prior to making a diagnosis of recurrent disease. The effects of immunosuppression may modify or delay disease expression within the graft. If PBC recurs, intermediate-term patient and graft survival is excellent, but long-term studies will be necessary to address the impact of disease recurrence on the allograft. Due to lack of a diagnostic gold standard, a diagnosis of recurrent PSC after transplantation is difficult to make. An accurate diagnosis of PSC recurrence requires well-defined cholangiographic and histologic criteria. Other disorders that can produce biliary strictures after transplantation should be excluded. As with PBC, the effects of immunosuppression may modify or delay disease expression within the graft; medium-term patient and graft survival is excellent. Recurrence of autoimmune hepatitis is based on clinical, biochemical, serologic, and histologic criteria. As in patients transplanted for PBC and PSC, other conditions that can mimic autoimmune hepatitis require exclusion prior to making a diagnosis of recurrence. Most adult recipients respond to an increase in immunosuppression, whereas pediatric recipients do not respond as well. A cautious approach to withdrawal of immunosuppression is warranted in all patients transplanted for autoimmune hepatitis and the consequences of recurrent disease within the graft will require prolonged follow-up. Future studies should focus on preventive and therapeutic strategies for recurrent autoimmune diseases after transplantation.     

Asymptomatic primary biliary cirrhosis

Four asymptomatic patients are described with raised serum alkaline phosphatase values and a positive serum mitochondrial antibody test. In all four needle liver biopsy showed destructive bile duct lesions. Lymphocyte transformation to phytohaemagglutinin was normal in three and impaired in one who also suffered from rheumatoid arthritis. Two patients showed normal skin and serological test responses to dinitrochlorobenzene and haemocyanin.These four patients are believed to be suffering from asymptomatic primary biliary cirrhosis.     

Weight loss in primary biliary cirrhosis.

Duodenal bile salt concentrations were measured throughout one day in six patients with primary biliary cirrhosis while they were eating a normal ward diet. Five of them had lost weight; none had ascites. Each patient had a radiologically normal small bowel and a normal jejunal biopsy. No clear relationship between high faecal fat excretion and abnormally low duodenal bile salt concentration was found. Xylose absorption was abnormal in five patients. If weight loss in primary biliary cirrhosis is due to malabsorption, factors other than a reduced small intestinal bile salt concentration must be important.     

Anticentromere antibody in primary biliary cirrhosis.

An autoantibody specific for the centromere region of chromosomes and recently detected in the serum of patients with scleroderma was found in ther serum of 10 (9.1%) of 110 consecutive patients presenting with primary biliary cirrhosis. It was found exclusively among those with scleroderma, giving a prevalence of 50% in that group, and all patients with telangiectasia or calcinosis had the antibody. It was not found in 80 patients with chronic active hepatitis, including the 'autoimmune' variety. The pathogenetic significance of anticentromere antibody is not yet established, but this study confirms its specificity for scleroderma in the context of primary biliary cirrhosis.     

Portal hypertension and primary biliary cirrhosis.

Portal hypertension has been regarded as an uncommon and late complication of primary biliary cirrhosis (PBC). 24 patients with PBC were investigated for portal hypertension. Esophageal varices were present in 20, 50, and 90% of the patients 1, 3, and 9 years, respectively, after the onset of pruritus and/or jaundice. Portal hypertension was responsible for gastrointestinal bleedings in 11 patients; bleeding was the first clinical manifestation of PBC in two of them. Wedged hepatic venous pressure was increased in all the patients with portal hypertension whether regenerative nodules were present or absent. Portacaval shunt was performed in five patients and was well tolerated in three of them. It is concluded that (a) portal hypertension is common in PBC; (b) the intrahepatic block is of the so-called postsinusoidal type, even in patients without regenerative nodules; (c) gastro-intestinal bleeding due to portal hypertension occurs in about half of the patients and may be the first manifestation of PBC; (d) portacaval shunt seems to be indicated when gastro-intestinal bleeding occurs in earlier stage of the disease.     

Rheumatic disorders in primary biliary cirrhosis.

Eighty-three patients with primary biliary cirrhosis were investigated to determine the prevalence of rheumatic disorders. 14 had scleroderma, which tended to be mild but in several patients produced severe systemic manifestations. The CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactyly, telangiectasia) was only identified twice. There was an increased incidence of HLA A1+B8 in those patients with scleroderma. As well as those with scleroderma, 4 patients had a destructive arthropathy resembling avascular necrosis. 4 patients had an inflammatory arthritis, without specific features, but the frequency was no greater than might be expected in the general population.     

Pediatric-onset primary biliary cirrhosis

Unlike other autoimmune liver diseases, primary biliary cirrhosis (PBC) has not been reported in childhood. We report 2 cases of PBC diagnosed at 16 and 15 years of age, respectively. The first girl was noted to have increased liver enzyme levels at 16 years of age. Antimitochondrial antibody (AMA) was strongly positive, and serum quantitative immunoglobulin M level was 8.26 g/L (normal, 0.6-3 g/L). A liver biopsy specimen showed stage II PBC. Despite treatment with ursodeoxycholic acid, she developed progressive cholestasis, intractable pruritus, and a significant sensory neuropathy and weight loss eventually requiring liver transplantation. Her mother had PBC/autoimmune overlap syndrome and underwent successful liver transplantation at 34 years of age. The second girl had persistently elevated liver enzyme levels following cholecystectomy at 15 years of age for symptomatic cholelithiasis. Endoscopic retrograde cholangiopancreatography showed no abnormalities. AMA was positive at 1:160, and serum quantitative immunoglobulin was 6.96 g/L. A liver biopsy specimen showed stage II PBC, and her liver enzyme levels almost normalized after starting treatment with ursodeoxycholic acid. In conclusion, we present 2 liver biopsy-confirmed cases of pediatric-onset AMA-positive PBC. With increased awareness of early-onset PBC, further pediatric cases may be discovered.     

Genetic susceptibility to primary biliary cirrhosis.

Family studies suggest that genetic factors play a role in determining susceptibility to primary biliary cirrhosis (PBC). A number of polymorphic genes with small and additive effects may thus encode factors predisposing to this 'polygenic' disease. All the published data on genetic predisposition to PBC have been obtained from association studies, based on comparison of the frequency of an allele in unrelated affected and unaffected individuals from a population; however, many studies have examined only small datasets. There is evidence from several different populations to support a role for the major histocompatibility complex (MHC) class II antigen, HLA DR8, in increased risk of PBC. Other 'candidate' genes, selected on the basis of postulated mechanisms of breakdown of self-tolerance, are now beginning to be tested in association studies, including cytokines and immunomodulatory molecules. These studies and other approaches to identifying genes that confer susceptibility to an autoimmune disorder, exemplified by PBC, are discussed.